This is an application for a consortium grant involving the laboratories of Dr. Utter (Biochemistry) and Dr. Kerr (Pediatrics) of Case Western Reserve University, School of Medicine and that of Drs. Atkin and Buist (Pediatric Metabolic Laboratory) of the University of Oregon Health Science Center. There is considerable evidence from these laboratories and others that there is a group of inherited metabolic diseases that involve enzymes concerned with pyruvate metabolism. This group of enzymes includes pyruvate carboxylase, phosphoenolpyruvate carboxykinase, pyruvate dehydrogenase complex and pyruvate kinase. Inborn errors affecting one of these enzymes may lead to lactic acidosis, hypoglycemia, renal tubular acidosis, and mental and developmental retardation. Although such enzymic deficiencies mainly affect liver, kidney and the nervous tissue, a major aim of this project is to develop reliable and valid assays for this group of enzymes which can be applied to fibroblasts, lymphocytes and platelets. Preliminary results suggest the feasibility of this goal. The assays will be applied to patients with lactic acidosis, renal tubular acidosis and certain neurological disturbances. The assays will also be used for genetic studies involving relatives of newly and previously discovered patients. Where evidence of an inborn error involving one of these enzymes is obtained, more extensive studies on the nature of the defect in the enzyme and its physiological significance will be undertaken. Dr. Utter's laboratory will have the primary responsibility for developing and validating the assays; that of Drs. Atkin and Buist for the application of the assays including the genetic studies, and both laboratories will be involved in elucidation of the nature of enzyme defects when these are found. One such case of pyruvate carboxylase deficiency is already under intensive study. Dr. Kerr as well as Drs. Atkin and Buist will undertake physiological studies on selected patients to evaluate the effect of specific inborn errors and carbohydrate and oxidative metabolism. Overall aims are to provide bases for diagnoses and genetic counseling in these diseases.